Spironolactone nanocrystals for oral administration: Different pharmacokinetic performances induced by stabilizers

Nanocrystal (NC) technology is an effective strategy to enhance the oral bioavailability for poorly water-soluble drugs. Stabilizers are essential and important in NC formulations due to its ability to decrease the system energy. Studies have revealed that stabilizers can affect the particle size and stability of the system. However, whether stabilizers can affect the in vivo behaviors of the NCs is unknown. To investigate the effects of stabilizers on the in vitro and in vivo performances of NCs, four types of spironolactone (SPN) NCs with similar diameters but different stabilizers were prepared. All the NCs were spherical in shape with a size of about 370nm. In addition, the NCs were also characterized by differential scanning calorimetry, X-ray diffraction, and Raman spectroscopy, the results obtained showed that the SPN in all the formulations was partially amorphous. In fasted state simulated intestinal fluid, all the SPN-NCs showed similar dissolution profiles. However, the dissolution for SPN-NCs/NaDC was suppressed in 0.1M HCl. Importantly, the AUC(0-48h)total for SPN-NCs/F127, SPN-NCs/F68, SPN-NCs/HPMC-E5, and SPN-NCs/NaDC was 4.96-, 3.91-, 2.88- and 1.72-fold higher than that of the SPN suspension, respectively. These results demonstrated that stabilizers in NCs played an important role for the in vivo pharmacokinetic behaviors. It is highly suggested that the ionic stabilizers are not suitable to stabilize drug nanocrystals alone because it may induce aggregation and agglomeration of drug crystals when transferring through the whole gastrointestinal tract and experiencing the different pH levels.